Derivatives of i-cholesterol



Patented June 30, 1942 DERIVATIVES or i-CHOLESTEROL Everett S. Wallis and Erhard Fernholz, Princeton,

N. J., assignors to Merck & Co., Inc., Rahway,- N. J a corporation of New Jersey No Drawing. Original application January 16, 1937, Serial No. 120,880, now Patent No.

2,205,448, dated June 25, 1940.

Divided and this application April 16, 1940, Serial No. 329,911

2 Claims.

This is a division of application Serial No. 120,880, filed January 16, 1937, now Patent No. 2,205,448 issued June 25, 1940.

This invention relates more particularly to the new compounds, i-cholestanone and i-cholestanone oxime, derivatives of i-cholesterol, the new compound disclosed in our co-pending application Serial No. 120,880.

These new compounds were prepared by us during the course of our investigations of new processes for the preparation of the epimeric modifications of certain unsaturated sterols.

The epimerization of the hydroxyl group of cholesterol, and other unsaturated sterols, has assumed considerable importance since Ruzicka, et al., [Helv. Chim. Acta. 17 1395 (1934)] reported their findings to the effect that the male hormone, androsterone, is a derivative of epidihydrocholesterol, and that its physiological activity is much greater than that of the corresponding epimer, iso-androsterone, obtained from 3-cholestano1.

Our method of approach to the preparation of epi-cholesterol, was based upon certain experiments reported by Phillips [J Chem. Soc. 123 44, (1925)], carried out on alcohols containing only one asymmetric carbon atom, and it involved an investigation of the action of potassium acetate on cholesteryl-p-toluene sulfonate. However, in order to avoid the complication of the formation of ethers, and since We had observed that, in acetic acid solution, the normal cholesteryl acetate is formed, our reaction was carried out with anhydrous potassium acetate in acetic anhydride solution. Very unexpectedly, a new, hitherto unknown, acetate was thus obtained, ,which is isomeric with cholesteryl acetate, and which we call i-cholesteryl acetate.

This new compound is strongly dextro-rotatory, [ul D=+47.8, and melts at about 73 C. On hydrolysis, it yields i-cholesterol. It crystallizes from alcohol in long needles which melt at roomtemperature. The substance resolidifies and passes into another crystalline form which melts at 74-75" C. The hydrolysis product, icholesterol, is also strongly dextro-rotatory [a] =|23.9. It is not precipitated by digitonin. Reacetylation yields the above i-cholesteryl acetate.

Hydrogenation of the new acetate is most satisfactorily accomplished by reacting upon it with the Adams platinum oxide catalyst. When this platinum oxide is reduced in the presence of the i-cholesteryl acetate, rapid hydrogenation takes place and dihydrocholesteryl acetate is formed in good yield; Palladium black was found to be ineffective for this purpose, while only a very slow reaction is obtained with platinum black.

Our new acetate, i-cholesteryl acetate, does not react with perbenzoic acid. It does not decolorize readily a solution of bromine in carbon tetrachloride. The Liebermann reaction is quite strong. This inertness toward bromine and per-, benzoic acid, and its relative stability toward catalytic hydrogenation suggest that a double bond, as such, is not present in i-cholesteryl acetate and i-cholesterol.

We have found that i-cholesterol may be easily oxidized with chromic acid in acetic acid solution. From the products formed, an oxime has been isolated, in 20% yield. This indicates that i-cholesterol is a secondary alcohol.

Preparation of i-cholesteryl acetate About 100 gms. of anhydrous potassium acetate are dissolved in 1500 cc. of boiling pure acetic anhydride. The solution is-cooled to 50 C., whereupon potassium acetate crystallizes in a finely divided state, About 35 gms. ,of cholesteryl-p-toluene sulfonate are added. The flask is then placed on the steam bath, and stirred for approximately 36 hours, during which time the temperature inside the flask is varied from -80 C.

The dark brown mixture is poured into cold water; 800 cc. of ether are added, and the ether layer is washed repeatedly with a cold aqueous solution of potassium carbonate. The acetic anhydride also may be removed by distillation under diminished pressure. After complete removal of the acetic anhydride and acetic acid, the ether layer is dried with anhydrous sodium sulfate, decolorized with animal charcoal and the ether removed by distillation. An oily product is obtained. This material is dissolved in alcohol, and small amounts of ether are added. Crystallization maybe carried out in such a manner as to obtain four crops of crystals:

Several recrystallizations of the 3rd and 4th fractions give 0.4 gms. of material having a meltmaterial.

ing point of 71 0., and 7.5 'gms. of a material melting at 67-68 C.

The i-cholesteryl acetate may be freed from cholesteryl acetate which occurs with it in the following manner:

About 7 gms. of i-cholesteryl acetate (M. P. 67-68 C.) are dissolved in 100 cc. of alcohol, and treated with 8 gms. of potassium hydroxide. The solution is refluxed for one-half hour on the water bath, then poured into water and extracted with ether. The dried ether solution is evaporated to dryness and taken up in a small amount of 90% alcohol. A solution of 6 gms. of digitonin in 500 cc. of 90% alcohol is then added. The contents are allowed to stand until they reach room temperature. The digitonide is filtered and dried.

The filtrate is evaporated to dryness and digested with ether. The ether solution is distilled and the residue is dissolved in alcohol. n cooling in an ice-salt mixture, i-cholesterol crystallizes. The crystals are filtered rapidly, and placed in a vacuum desiccator. They melt and resolidify. Weight of product, 3.5 gms.; melting point, Pl-75 C.

About 22.6 mg. of this material dissolved in 2 cc. of chloroform solution gave aD=+0.27 (100 mm. tube) [a] =+23.9.

About gms. of i-cholesterol is heated with 10 cc. of acetic anhydride for about one hour on the water bath. On cooling, a crystalline product separates. Recrystallization from alcohol gives an acetate which melts at 73 C.

About 25.1 mg. in 2 cc. chloroform solution gave ozD=+0.6. [a] D=I-47.8.

Oxidation of i-cholesterol with chromic acid About ninety-three hundredths of a gram of i-cholesterol is dissolved in 30 cc. of specially purified acetic acid (KMNOi method). A solution of 0.64 gm. of chromic acid in cc. of acetic acid is added drop-by-drop The solution becomes temporarily cloudy, and the temperature rises slightly. The mixture is kept at room temperature for about 12 hours, and is then extracted with ether. The ether is shaken with an aqueous solution of 2 N sodium hydroxide to remove acidic This acidic material cannot be crystallized. The neutral part crystallizes as i-cholestanone. It forms an oxime.

Preparation of the oxime where R may be selected from the group consisting of an acetate radical, hydroxyl, oxygen, and the oxime radical.

We claim as our invention:

1. icholestanone of the following formula:

CH3 CH5 CH3 CH3 JH-CH CHzOHZCH CHi 2. The process comprising hydrolyzing the product of reaction between cholesteryl-p-toluene sulfonate and anhydrous potassium acetate in acetic anhydride, and oxidizing the hydrolysis product with chromic acid.

EVERETT S. WALLIS. ERHARD FERNHOLZ. 

